1. Field of the Invention
The invention relates to saccharin derivatives which inhibit the enzymatic activity of proteolytic enzymes, to processes for preparation thereof, to method of use thereof in treatment of degenerative diseases and to pharmaceutical compositions thereof.
2. Information Disclosure Statement
Inhibitors of proteolytic enzymes are useful in treatment of degenerative disorders such as emphysema, rheumatoid arthritis and pancreatic in which proteolysis is a substantive element. Serine proteases are the most widely distributed class of proteolytic enzymes. Some serine proteases are characterized as chymotrypsin-like or elastase-like based upon their substrate specificity. Chymotrypsin and chymotrypsin-like enzymes normally cleave a peptide bond in a protein at a site at which the amino acid on the carbonyl side is Trp, Tyr, Phe, Met, Leu or other amino acid which contains an aromatic or a large alkyl side chain. Elastase and elastase-like enzymes normally cleave a peptide bond at a site at which the amino acid residue on the carbonyl side of the bond is Ala, Val, Ser, Leu or other small amino acid. Both chymotrypsin-like and elastase-like enzymes are found in leukocytes, mast cells and pancreatic juice in higher organisms, and are secreted by many types of bacteria, yeast and parasites.
Dunlap et al. PCT Application WO 90/13549 published Nov. 15, 1990 describes a series of 2-substituted saccharin derivatives useful as proteolytic enzyme inhibitors.
Barber et al., U.S. Pat. No. 2,855,401, issued Oct. 7, 1958, disclose compounds of the formula: ##STR2## wherein R.sub.1 and R.sub.2 are each selected from hydrogen, lower-alkyl and lower hydroxyalkyl, n is an integer from 5 to 9 and R.sub.3 is a group selected from methanesulphonamido, benzenesulphonamido and o-sulphonbenzimido. The compounds are said to be useful in the treatment of bilharziasis.
Brown et al., U.S. Pat. No. 3,220,940, issued Nov. 30, 1965, disclose the use in acidic nickel baths of the compounds of the formula: ##STR3## or the Ni, Na, Co, K, Li, Mg, etc. sulfonate salts thereof, wherein A is selected from the group consisting of the benzene, biphenyl and napthalene rings, R is selected from the group consisting of H, OH, Cl, Br, SO.sub.3 H and CH.sub.3, n is an integer from 1 to 4 inclusive, n.sub.1 is 0 or 1, n.sub.2 is zero, 1 or 2, and when n.sub.2 is zero then n1 is zero.
Sunket et at., European Patent Application 253092, published Jan. 20, 1988, disclose 2-saccharinyl-lower-alkyl-1,4-dihydropyridine-3-carboxylates having platelet aggregation inhibitory and antithrombotic activities. A substantially similar disclosure can be found in Sunket et al., J. Med. Chem. 31, 1886-1890 (1988).
Mulvey et al., U.S. Pat. No. 4,195,023, issued Mar. 25, 1980, disclose R.sub.1 -2-R.sub.2 CO-1,2-benzisothiazol-3-ones, where R.sub.1 is halogen, alkoxy, alkylamino, dialkylamino, alkoxycarbonyl, amino, nitro or hydrogen in the benzenoid ring and R.sub.2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halophenyl, heteroaryl or substituted heteroaryl R.sub.1 -2-A-CO saccharins, where R.sub.1 has the same meanings as the benzenoid ring substituents in the 1,2-benzisothiazol-3-ones and A is alkyl, alkenyl, alkynyl, cycloalkyl, fluorophenyl, heteroaryl or substituted heteroaryl. The compounds are said to have elastase inhibitory activity and to be useful in the treatment of emphysema. A similar disclosure is found in French Patent 2,321,288, published Mar. 18, 1977.
Dunlap et al., European Patent Application 483928A1, published May 6, 1992, disclose 4-R.sup.4 -R.sup.5 2-saccharinylmethyl aryl carboxylates and 4,5,6,7-tetrahydro-2-saccharinylmethyl aryl carboxylates which are said to have protease enzyme inhibitory activity and be useful in the treatment of degenerative diseases. A similar disclosure is found in Dunlap et at., U.S. Pat. No. 5,128,339, issued Jul. 7, 1992.
Jones et at., U.S. Pat. No. 4,276,298, issued Jun. 30, 1981, disclose 2-R-1,2-benzisothiazolinone-1,1-dioxides, where R is phenyl substituted by fluoro, dinitro, trifluoromethyl, cyano, alkoxycarbonyl, alkylcarbonyl, carboxyl, carbamoyl, alkylacylamino, alkylsulfonyl, N,N-dialkylsulfamoyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfonyl and trifluoromethylsulfinyl or pyridyl substituted the same as R when R is phenyl except that pyridyl may also be mononitro substituted. The compounds are said to have protease enzyme inhibitory activity, especially elastase inhibitory activity, and to be useful in the treatment of emphysema, rheumatoid arthritis "and other inflammatory diseases."